rs2303995

Variant names:

• chr8-132163489-T-C
• rs2303995
• NM_004519.4:c.1241A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004519.4(KCNQ3):​c.1241A>G​(p.Glu414Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,611,190 control chromosomes in the GnomAD database, including 1,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (134 hom., cov: 33)
  • Exomes 𝑓: 0.027 (1213 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 3.49
• Publications: 21 publications found

Genes affected

KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

KCNQ3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• self-limited familial neonatal epilepsy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign neonatal seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017500818).
• BP6: Variant 8-132163489-T-C is Benign according to our data. Variant chr8-132163489-T-C is described in ClinVar as Benign. ClinVar VariationId is 21409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004519.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	NM_004519.4	MANE Select	c.1241A>G	p.Glu414Gly	missense	Exon 9 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.881A>G	p.Glu294Gly	missense	Exon 9 of 15	NP_001191753.1	O43525-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.1241A>G	p.Glu414Gly	missense	Exon 9 of 15	ENSP00000373648.3	O43525-1
	KCNQ3	ENST00000519445.5	TSL:5	c.1241A>G	p.Glu414Gly	missense	Exon 9 of 15	ENSP00000428790.1	E7ET42
	KCNQ3	ENST00000521134.6	TSL:2	c.881A>G	p.Glu294Gly	missense	Exon 9 of 15	ENSP00000429799.1	O43525-2

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3752 AN: 152188 Hom.: 136 Cov.: 33

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.0354 AC: 8886 AN: 251066 AF XY: 0.0338

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.0412

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.170

Gnomad FIN exome AF: 0.0371

Gnomad NFE exome AF: 0.0224

Gnomad OTH exome AF: 0.0276

GnomAD4 exome AF: 0.0273 AC: 39844 AN: 1458882 Hom.: 1213 Cov.: 29 AF XY: 0.0270 AC XY: 19573 AN XY: 726072

African (AFR) AF: 0.00305 AC: 102 AN: 33444

American (AMR) AF: 0.0396 AC: 1770 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0255 AC: 667 AN: 26110

East Asian (EAS) AF: 0.200 AC: 7940 AN: 39634

South Asian (SAS) AF: 0.0169 AC: 1461 AN: 86200

European-Finnish (FIN) AF: 0.0365 AC: 1947 AN: 53392

Middle Eastern (MID) AF: 0.00729 AC: 42 AN: 5764

European-Non Finnish (NFE) AF: 0.0219 AC: 24304 AN: 1109340

Other (OTH) AF: 0.0267 AC: 1611 AN: 60290

GnomAD4 genome AF: 0.0246 AC: 3747 AN: 152308 Hom.: 134 Cov.: 33 AF XY: 0.0267 AC XY: 1985 AN XY: 74482

African (AFR) AF: 0.00476 AC: 198 AN: 41576

American (AMR) AF: 0.0254 AC: 388 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3470

East Asian (EAS) AF: 0.175 AC: 904 AN: 5178

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4824

European-Finnish (FIN) AF: 0.0361 AC: 383 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0241 AC: 1642 AN: 68020

Other (OTH) AF: 0.0194 AC: 41 AN: 2116

Alfa AF: 0.0265 Hom.: 314

Bravo AF: 0.0238

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0224 AC: 193

ExAC AF: 0.0340 AC: 4126

Asia WGS AF: 0.0780 AC: 271 AN: 3478

EpiCase AF: 0.0198

EpiControl AF: 0.0210

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Benign Neonatal Epilepsy (1)
-	-	1	Benign neonatal seizures (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	Seizures, benign familial neonatal, 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.024
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.48	T
PhyloP100		3.5
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.35
Sift	Benign	0.032	D
Sift4G	Benign	0.14	T
Polyphen		0.12	B
Vest4		0.50
MPC		1.1
ClinPred		0.019	T
GERP RS		4.6
Varity_R		0.20
gMVP		0.70
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2303995; hg19: chr8-133175736; COSMIC: COSV66474926;